1. Field of the Invention
The present invention is drawn to endothelial-derived interleukin-8 (IL-8). These polypeptides, previously identified as "leukocyte adhesion inhibitor" (LAI), are involved in the process through which populations of leukocytes are inhibited from adhering to cellular substrates. The invention additionally relates to the use of endothelial-derived IL-8 as anti-inflammatory agents and as therapeutics for clinical indications in which damage of vascular endothelium and other tissues occurs.
2. Description of the Related Art
When foreign invaders such as bacteria, viruses or other invading parasites penetrate the skin or mucous membranes, cellular defense mechanisms are immediately induced. Local and blood-borne monocytes and polymorphonuclear leukocytes (PMN), two of the phagocytic-type cells of the defense system, accumulate around the invaders and initiate phagocytosis. An excellent review of the defense system is provided by Eisen, H. W., In: Microbiology, Third Ed., Harper and Row, Philadelphia, Pa. (1980), pp. 290-295 and 381-418.
The presence of such foreign entities results in an inflammatory response characterized by (1) dilation of surrounding blood vessels; (2) an increase in vascular permeability; and (3) diapedesis, the migration of monocytes and PMN across vascular walls.
The accumulation of blood leukocytes at sites of inflammation and injury depends upon their localized adhesion to the vascular lining. Localized adhesion is essential in a variety of pathophysiological processes. Leukocytes must be able to attach to cellular substrates in order to properly defend the host against these invaders. They must also attach to endothelial cells so that they can migrate from the circulation to sites of ongoing inflammation. Furthermore, they must attach to antigen-presenting cells so that a specific immune response can occur. Finally, they must attach to appropriate target cells so that lysis of virally-infected or tumor cells can occur.
The adherence of leukocytes to vascular endothelium in areas of inflammation and injury has long been known. It has also long been suspected that molecular changes in the blood vessel wall are involved in these endothelial-leukocyte interactions. However, experimental evidence supporting this concept was lacking until recently (see Harlan, J., Blood 65:513-525 (1985)).
Recent studies have demonstrated that certain inflammatory cytokines such as Interleukin-I (IL-1) (see, e.g., Bevilacqua et al., J. Clin. Invest. 76:2003-2011 (1985); Bevilacqua et al., In: Leukocyte Emigration and Its Sequelae, S. Karger, AG, Basel and New York, pp. 79-93 (1986); Dunn et al., In: The Physiologic, Metabolic, and Immunologic Actions of Interleukin-1, Alan R. Liss, Inc., New York, pp. 45-59 (1985); Schleimer et al., J. Immunol. 136:649-654 (1986); Gamble et al., PNAS U.S.A. 82:8667-8671 (1985); Pohlman et al., J. Immunol. 136:4548-4553 (1986) ; Cavender et. al., Fed. Proc., 46:113-117 (1987)), tumor necrosis factor (TNF) (Gamble et al., PNAS U.S.A. 82:8667-8671 (1985)), and Gram-negative bacterial endotoxin (lipopolysaccharide) (LPS) (Schleimer et al., (1986); Pohlman et al., J. Immunol. 136:4548-4553 (1986)) can act directly on vascular endothelium in vitro to increase the adhesiveness of the endothelial cell surface for blood leukocytes as well as the related leukocyte cell lines (HL-60 and U937).
Other chemotactic factors, such as purified complement components, formyl-methionyl-leucyl-phenylalanine, and leukotriene B.sub.4 can also augment the attachment of PMN to cultured endothelial monolayers (see, e.g., Smith et al., Exp. Cell Res. 122:169-177 (1979); Hoover et al., J. Cell Sci. 45:73-86 (1980); Hoover et al., PNAS U.S.A. 81:2191-2193 (1984); Zimmerman et al., Thromb. Res. 35:203-217 (1984); Gimbrone et al., J. Clin. Invest. 74:1552-1555 (1984); Tonnesen et al., J. Clin. Invest. 74:1581-1592 (1984); Charo et al., Blood 65:473-479 (1985); Harlan et al., Lab. Invest. 52:141-150 (1985)). The relative significance of endothelial versus leukocyte responses, and the cellular mechanisms involved in their adhesion, however, are still largely unknown.
The inhibition of leukocyte adhesion potentially is of central importance to therapeutic interventions in inflammatory disease processes. Although leukocyte adhesion is normally desirable, it is also implicated in immune and non-immune inflammatory disease processes, including organ transplant rejection, tissue graft rejection, allergic reactions, autoimmune diseases, rheumatoid arthritis, vasculitis, septic shock, adult respiratory distress syndrome (ARDS), glomerulonephritis, and other tissue or organ specific forms of acute and chronic inflammation. Further, in the setting of ischemiareperfusion, leukocyte adhesion may produce microvascular occlusion, tissue injury and death. Hence, any means capable of attenuating or inhibiting cellular adhesion would be highly desirable for certain patients.